Process of separating doisynolic acids and intermediates therefor



Patented May 3, 1949 PRGCESS F SEPARATING DOISYNOLIC ACIDS AND HNTERMEDIATES THEREFOR Karl Miescher, Riehen, and Rudolf Rometsch,

Basel, Switzerland, assignors to Ciba Pharmaceutical Products, Inc., Summit, N. J.

No Drawing. Application April 22, 1947, Serial No. 743,194. In Switzerland April 30, 1946 8 Claims. 1

The present invention relates to esters of optically active alcohols with acids of the doisynolic type, and to a method for the preparation of such esters in a mannerenabling the separation thereof into their pure optical antipodes.

'Copending applications, Ser. No. M2512, filed June '29, 1944, now Patent No. 2,459,334, dated Jan. 25, 19 l9, and Ser. No. 622,092, filed October '12, 1945, now Patent No. 2,459,949, dated Jan. 25, 1949, disclose processes for the preparation of hydrophenanthrene carboxylic acids and derivatives thereof which, owing to the asymmetrical character of their ring structure, occur in the form of racemic isomers, of which one may possess an especially powerful estrogenic activity. Thus, by the aforesaid processes, it is possible to isolate, amon others, two racemic l-ethyl-2- methyl-"Z-hydroxy 122:3:4 tetrahydrophenanthrene-2-carboxylic acids, namely the nand isobisdehydro-doisynolic acids. While for the normal acid the threshold value in the estrus test on rats amounts only to 0.1-0.15 on oral administration and to 0.?--0.2 on subcutaneous application, the diastereoisomeric acid has proved to be wholly inactive. The levo-rotary compound corresponding to the racemic n-bisdehydro-doisynolic acid has been prepared by alkaline fusion of d-equilenin [see Heer, Billeter and Miescher, Helvetica Chimica Acta, vol. 28, pages 991-1003 (1945) l, and exhibits a threshold value of 0.05-0.1 on oral administration in the estrus test on rats. This compound is therefore about twice .as active as the synthetically prepared racemate and is the most active estrogenic compound hitherto known.

However, no process has hitherto become known which enables racemic acids of the type of doisynolic acid or derivatives thereof to be separated into their pure optical antipodes.

A primary object of the present invention is the preparation of compounds, more particularly esters, of optically active alcohols with acids of the doisynolic type, which compounds are readily separable into their pure optical antipodes.

A further object of the invention is the embodiment of a process whereby racemic acids of the type hereinbefore described may successfully be obtained in the form of the separated pure optical antipodes.

It has been found that the aforesaid objects may be realized by taking advantage of the discovery that when racemic acids of the doisynolic acid type or reactive derivatives thereof, wherein the phenolic hydroxyl group is protected, are subjected to the action of optically active alcohols,

the resultant two diastereoisomers are readily separable from each other, so that the esters are thus obtainable in .the .form of their separated pure optical antipodes. The racemic acids themselves, in the formof their separated pure optical antipodes, may then .be produced by treating the aforementioned separated diastereoisomers with agents capable of converting the esterified carboxyl group and/or the protected phenolic hydroxyl group into .iree carboxyl and hydroxyl groups, respectively.

The phenolic hydroxyl group .of the racemic acids, such as n-bisdehydr.o-doisynolic acid, may be protected, for example, by etherification with methanol, ethanol, a phenol, a benzyl alcohol or the like, or by esterification with an organic or inorganic acid. The starting materials may be prepared, for example, .in the manner described in the aforesaid copending applications.

The conversion into the esters in accordance with the invention may be eiiected with any of the known readily accessible optically active alcohols, such as borneol, terpineol or tetrahydronaphthol, and above all with dor l-menthol. For example, menthyl esters of racemic n-7- methyl-bisdehydro-doisynolic acid can be obtained by heating the corresponding acid chloride with menthol to C. in a current of nitrogen. However, the same result can be realized by other I methods of esteriiication. The .two optically active isomers so formedcan beobtained in the pure state by recrystallization. Instead of by systematic crystallizations, complete separation of the diastereoisomeric forms may also be effected by means of chromatographic adsorption methods.

The new esters so obtained may then be treated with agents which convert the esterified carboxyl group and/or the protected phenolic hydroxyl group into a free carboxyl and .hydroXyl group, respectively. For this ,purpose, usemay be made of conventional hydrolyzing agents or of pyridine salts or the like. When, for example, it .isdesired only to hydrolyze the esterified .carboxyl groupof an ether-ester, use is suitably made of alkaline agents such as a potassium hydroxide melt with propyl alcohol and a low water content. Subsequently or simultaneously, an etherified or esterifled phenolic hydroxyl group may also be hydrolyzed. When a benzyl roup or the like is to be split ed, a reducing agent may equally well be used.

optically active acidsoi the doisynolic acid type thus obtained .-may, if desired, be esterified or etherified at the=oarboxyl .and/ or phenolic hydro-xyl groups.

The products of the invention are useful for therapeutic purposes or serve as intermediate products for making therapeutically valuable compounds.

The following example illustrates the invention, the parts being by weight unless otherwise stated and the relationship of parts by weight to parts by volume being the same as that of the kilogram to the liter:

Example 8 parts of racemic n-7-methyl-bisdehydrodoisynolic acid chloride, that is, the '7-methyl ether of n-bisdehydro-doisynolic acid (obtained, for example, by the action of oxalyl chloride on the methyl ether meltingat 228-230 C. of racemic n-bisdehydro-doisynolic acid melting at 204 C.) are heated at 100-110 C. with an equivalent quantity of l-menthol for a few hours in a current of nitrogen. The resulting hydrogen chloride is removed from the reaction mixture by means of the current of nitrogen.

When triturated with methanol the cooled melt crystallizes immediately, It is finely pulverized and washed with a small quantity of methanol in order to remove the excess of menthol. The product is then dissolved in a minimum amount of hot absolute acetone and allowed to crystallize at 20 C. The first fraction of crystals so obtained consists of almost pure -n-7 methyl bisdehydro doisynolic acid l-menthyl ester. From the mother liquor there is obtained after concentration to 30 parts by volume a second fraction of crystals of approximately the same composition as the first crystallizate. Both fractions are recrystallized together from absolute acetone. In this manner pure -n-7- methyl-bisdehydro-doisynolic acid l-menthyl ester is obtained melting at 163-464 C. and exhibiting the rotation [oc] =-i1 (ethyl acetate, 0:1.18).

In order to obtain the -n-"l-methyl-bisdehydro-doisynolic acid l-menthyl ester, the mother liquor from the second crystallization is evaporated to dryness, and the residue is recrystallized from 450 parts by volume of methanol. There are obtained colorless crystals melting at 112 C. and exhibiting the rotation [a] :64i1.5.

The two diastereoisomeric menthyl esters melting at l63-164 C. and 112 C. respectively, may be severally hydrolyzed, for example, by being heated for one hour at 165 C. in a melt contain ing, for each part of the ester, 2.5 parts of potassium hydroxide'and 8 parts by volume of propyl alcohol. No racemization occurs. Also, by starting from extensively concentrated acids obtained by hydrolysis of the not entirely pure menthyl esters, the pure antipodes can be obtained by recrystallizing one to three times from mixtures of methanol and water. The (+)-n-7-methylbisdehydro-doisynolic acid and -n-7-rnethyl bisdehydro-doisynolic acid so obtained have the following properties:

The levo-rotary acid produces no lowering of the melting point in admixture with the methyl ether of the n-bisdehydro-doisynolic acid obtained from d-equilenin by means of a potassium hydroxide melt. It can be converted into the optically active free hydroxy-acid, for example, by heating it with pyridine hydrochloride. The free hydroxy-acid can also be obtained by the direct hydrolysis of the corresponding methoxymenthyl ester.

Instead of the methyl ether of n-bisdehydrodoisynolic acid, another ether or an ester, such as the acetate or propionate, may be used as starting material.

In an analogous manner it is possible to separate the racemates of 7-hydroxy-1-ethylidene-2- methyl 1 :2:3 :4 tetrahydrophen-anthrene-(2) carboxylic acid, the 7-hydroxy group of which may be protected by etherification or esteriflcation.

From the resulting acids there may also be obtained esters, for example, the two n-7-methylbisdehydro-doisynolic acid methyl esters melting at 107-108 C.

Having thus described the invention, what is claimed is:

1. In a process for the production of the separated pure optical antipodes of optically active compounds, the step of treating a member of the group consisting of a racemic doisynolic acid and reactive derivatives thereof, wherein the phenolic hydroxyl group is protected, with an optically active alicyclic alcohol, whereby a mixture of separable diastereoisomers is produced.

2. A process for the production of the separated pure optical antipodes of optically active esters, which comprises treating a member of the group consisting of a racemic doisynolic acid and reactive acid derivatives thereof, wherein the phenolic hydroxyl group is protected, with an optically active alicyclic alcohol, whereby a mixture of separable diastereoisomeric esters is produced, and separating the said mixture into its component optically active esters.

3. A process for the production of the separated pure optical antipodes of optically active esters, which comprises treating a member of the group consisting of a racemic doisynolic acid and reactive acid derivatives thereof, wherein the phenolic hydroxyl group is protected, with an optically active alicyclic alcohol, whereby a mixture of separable diastereoisomeric esters is produced, and separating the said mixture into its component optically active esters by fractional crystallization.

4. A process for the production of the separated pure optical antipodes of optically active acids, which comprises treating a member of the group consisting of a racemic doisynolic acid and reactive acid derivatives thereof, wherein the phenolic hydroxyl group is protected, with an optically active alicyclic alcohol, whereby a mixture of separable diastereoisomeric esters is produced, separating the said mixture into its component optically active esters, and treating the said esters with a hydrolyzing agent in order to convert the same into the corresponding acids.

5. A. process for the production of the separated pure optical antipodes of the optically active menthyl esters of 7-methyl-bisdehydro-doisynolic acid, which comprises treating racemic 7-methylbisdehydro-doisynolic acid with optically active menthol, whereby a mixture of separable diastereoisomeric menthyl esters of the said acid is formed, and separating the said mixture into its component optically active esters.

6. A process for the production of the separated pure optical antipodes of the optically active menthyl esters of 7 -methyl-bisdehydro-doisynolic v6 8. A member of the group consisting fif the dand l-methyl esters of the -.and -n- 7-methy1-bisdehydro-doisynolicnacids.

KARL MIESCHER. RUDOLF \ROMETSCH.

No references cited.

Certificate of Correction Patent No. 2,469,173. May 3, 1949.

KARL MIESCHER ET AL.

It is hereby certified that errors appear in the printed specification of the above numbered patent requiring correction as follows:

Column 5, line 8, claim 7, before lower-alkyl insert the numeral 7 column 6, line 2, claim 8, for l-methyl read I-menthyl;

and that the said Letters Patent should be read with these corrections therein that the same may conform to the record of the case in the Patent Office.

Signed and sealed this 4th day of October, A. D. 1949.

THOMAS F. MURPHY,

Assistant Oommim'mer of Patents. 

